Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors. It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (μ), delta (δ) and kappa (κ), have distinct pharmacological profiles, anatomical distributions and functions. See, for example: Wood, P. L., Neuropharmacology, 21, 487–497, 1982; Simon, E. J., Med. Res. Rev., 11, 357–374, 1991; Lutz et al., J. Recept. Res. 12, 267–286; and Mansour et al., Opioid I, ed. Herz, A. (Springer, Berlin) 79–106, 1993. The δ receptors are abundant in the CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The μ receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects. The κ receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking, water balance, food intake, tussis, gut motility, temperature control and various endocrine functions. They also produce analgesia. See, for example: Leander et al., J. Pharmacol. Exp. Ther. 234, 463–469, 1985; Morley et al., Peptides 4, 797–800, 1983; Manzanares, et al., Neuroendocrinology 52, 200–205, 1990; and Iyengar et al., J. Pharmacol. Exp. Ther, 238, 429–436, 1986; and U.S. Pat. No. 6,177,438.
Most clinically used opioid analgesics, such as morphine and codeine, act as μ receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds that are κ-receptor agonists act as analgesics through interaction with κ opioid receptors. The advantage of these agonists over the classical μ receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds that act as agonists at κ opioid receptors have been described in the art including the following illustrative classes of compounds:                U.S. Pat. No.4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds allegedly having analgesic activity.        U.S. Pat. No. 4,145,435 discloses N-(2-amino-cycloaliphatic)-phenylacetamide compounds allegedly having analgesic activity and narcotic antagonist activity.        U.S. Pat. No. 4,098,904 discloses N-(2-amino-cycloaliphatic)-benzoamides and naphthamides allegedly useful for relieving pain.        U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives allegedly having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.        U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides allegedly useful as analgesic and having low abuse liability.        U.S. Pat. No. 4,438,130 discloses 1-oxa-, aza- and thia-spirocyclic compounds allegedly having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.        U.S. Pat. No. 4,663,343 discloses substituted naphthalenyloxy-1,2-diaminocyclohexyl amides allegedly useful as analgesics.        U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides allegedly having high κ-opioid affinity, selectivity and potency and allegedly useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.        U.S. Pat. No. 5,532,266 discloses arylacetamides allegedly having high κ-opioid affinity useful as pharmaceutical agents for providing an analgesic effect and/or neuroprotective effect.        U.S. Pat. No. 5,688,955 discloses substituted piperidines, substituted naphthalenes, aryl-substituted amides, and cyclohexyl-substituted amides having κ opioid agonist activity, compositions containing them and methods of using them as analgesics.        U.S. Pat. No. 5,804,595 discloses amino acid conjugates of substituted 2-phenyl-N-[1-(phenyl)-2-(1-heterocycloalkyl- or heterocycloaryl-)ethyl]acetamides allegedly useful for selectively agonizing κ opioid receptors in mammalian tissue.        
There is still an unfulfilled need for compounds with κ opioid receptor activity that may be used in methods to provide beneficial pharmaceutical characteristics while minimizing undesirable side effects generally associated with administering exogenous opioids. The present invention is directed to these, as well as other important ends.